임신 중 흡연 노출 평가-곽호석
TRANSCRIPT
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임신 중 흡연 노출 평가를 위한
바이오 마커 개발
진단검사의학과곽호석
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Tobacco smoke
• Tobacco smoke component: > 5,000 chemi-
cals
• Electronic database of smoke components:
>2,000 chemicals
–Mainstream smoke: 542 chemicals
• Human inhalation risk: 98 chemi-
calsA list of smoke components needs to be selected with a suffi-ciently broad chemical, toxicological, and pharmacological pro-file.
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List of harzardous tobacco smoke compo-nents
Int. J. Environ. Res. Public Health 2011, 8
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Int. J. Environ. Res. Public Health 2011, 8
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Hazardous tobacco smoke component
• The list of Hoffmann analytes: biolog-
ically or toxicologically active main-
stream smoke components
– Based on research from the early 1990s
– Only includes carcinogens
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The list of Hoffmann analytesGroup Analytes Average Yields
Aromatic Amines
1-Aminonaphthalene (ng/cig) 15.1
2-Aminonaphthalene (ng/cig) 10.3
3-Aminobiphenyl (ng/cig) 3
4-Aminobiphenyl (ng/cig) 1.7
Carbonyls
Methyl ethyl ketone (μg/cig) 62.72
Acetaldehyde (μg/cig) 560.48
Acetone (μg/cig) 264.74
Acrolein (μg/cig) 58.77
Butyraldehyde (μg/cig) 29.58
Crotonaldehyde (μg/cig) 16.18
Formaldehyde (μg/cig) 21.61
Propionaldehyde (μg/cig) 43.92
Phenols
Catechol (μg/cig) 37.9
Hydroquinone (μg/cig) 32.4
m+p-Cresol (μg/cig) 5.84
o-Cresol (μg/cig) 1.89
Phenol (μg/cig) 7.32
Resorcinol (μg/cig) 0.91
Polycyclic Aromatic Hydrocarbon (PAH)
Benzo[a]pyrene (ng/cig) 7
Group Analytes Average Yields
Inorganics
Ammonia (μg/cig) 11.02
Hydrogen Cyanide (μg/cig) 109.2
Nitric Oxide (μg/cig) 223.41
Carbon Monoxide (mg/cig) 11.96
Organics Acrylonitrile (μg/cig) 8.28
Volatile Hydrocarbons
1,3-Butadiene (μg/cig) 29.94
Benzene (μg/cig) 43.39
Isoprene (μg/cig) 297.68
Toluene (μg/cig) 64.91
Styrene (μg/cig) 5.11
Nitrogen Hetero-cyclics
Pyridine (μg/cig) 7.02
Quinoline (μg/cig) 0.23
Nicotine (mg/cig) 0.75 (750ug)
Metals & Metalloids
Arsenic (ng/cig) 10.4
Cadmium (ng/cig) 47.8
Chromium (ng/cig) 73
Lead (ng/cig) 33
Mercury (ng/cig) 3.82
Nickel (ng/cig) 5.12
Selenium (ng/cig) 34.9
Tobacco Specific Nitrosamines (T-
SNAs)
NAB (ng/cig) 16.3 (0.016ug)
NAT (ng/cig) 119 (0.119ug)
NNK (ng/cig) 115.6 (0.116ug)
NNN (ng/cig) 133.1 (0.133ug)
'Tar' Nicotine-free-dry-particu-late-matter (mg/cig) 8.91
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Biomarkers of tobacco smoke ex-posure
• Carbon monoxide (CO)• Nicotine metabolite: Cotinine• Polycyclic aromatic hydrocarbon
(PAHs) metabolite: 2-naphthol, 3-hy-droxyfluorenes, 1-hydroxypyrene
• Tobacco specific nitrosamines (TSNAs) metabolite: NNAL
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Tobacco-specific nitrosamines(TSNAs)
Processed tobaccos are invariably contaminated with TSNAs.
Formed during processing (drying and fermentation)
Not present in fresh and green tobaccos
Different types of tobacco contain different concentrations of ni-
trosamines
The higher the nitrate content of tobaccos the higher also the nitrosamine con-
tamination
The high-nitrate tobaccos or other dark tobacco types are high in TSNAs
No correlation between the declared tar content of cigarettes and
the TSNA concentration in mainstream tobacco smoke
No evidence that nicotine is nitrosated during the smoking process
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Range for tar, nicotine and tobacco specific ni-trosamine (TSNA) in tobacco for commercial ciga-
rettes from several countries
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Results of testing for NNK yields from three brands of cigarettes in various countries
We see these results as a compelling and urgent argument for government regulation of carcinogen concentrations in ciga-rettes.
Tobacco Control 2000;9:351–354
Nicotine yield range
0.85 mg/cig to 1.3 mg/cig 0.68 mg/cig to 1.25 mg/cig
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Chemical structure of TSNAs
Nitrosation
Nitrosamine structure
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Formation of tobacco-specific nitrosamines in tobacco
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Potential third-hand smoke
PNAS ∣ April 13, 2010 ∣ vol. 107 ∣ no. 15
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The metabolic activation and inactivation of NNK
* 11β-HSD: 11β-hydroxysteroid dehydrogenase
Steroid hormonesDrug: diureticsDrug: block 11β-HSDDrugDrug: flavonoidFlavanone
Similar structure: hormones
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Chemical structure of NNAL
11β-HSD
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Metabolism of NNK and NNAL and formation of adducts
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Structures of characterizedpyridyloxobutyl DNA adducts
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Proposed activation pathways for NNN, NNK and NNKOAc
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Postulated metabolic pathway medi-ating the toxicity of NNK
Other chemi-cal in smoke
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Concentrations of total urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) (pg/mg creatinine) and ciga-
rettesper day in 1054 National Health and Nutrition Examination
Survey2007–2008 smokers
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Adjusted geometric means in regression model with 95%
confidence intervals.
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The metabolic activation and inactivation of NNK
* 11β-HSD: 11β-hydroxysteroid dehydrogenase
Steroid hormonesDrug: diureticsDrug: block 11β-HSDDrugDrug: flavonoidFlavanone
Similar structure: hormones
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Relationships between Cigarette Con-sumption and Biomarkers of Tobacco
Toxin ExposureCO
NNAL Cotinine
1-HOP (PAHs metabolite)
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Structures of NNK, NNAL, and NNAL-Gluc
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Quantitation of Metabolites of NNK af-ter Cessation of Smokeless Tobacco Use
Time post-cessation (days)
Smokeless tobacco Smoking
NNAL t1/2: 10-18 days > cotinine t1/2 : 1days
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Metabolizer phenotypes for smok-ers
• PM: poor metabolizer (ratio<2)• IM: intermediate metabolizer (ratio between 2 and 5)• EM: extensive metabolizer (ratio >5)
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Comparison of free, conjugated and total urinary NNAL for 60 smokers
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NNAL as a Biomarker of exposure to cigarette smoke at the preg-
nancy
• Smoking patterns during pregnancy
• Second hand smoke during preg-
nancy
• Fetal exposure
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Smoking patterns during preg-nancy
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Exposure to different sources of second-hand smoke during pregnancy and its effect on urinary cotinine and NNAL con-
centrations
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TOBACCO SMOKING OR EXPOSURE TO SECOND-HAND SMOKE ON THE LEVELS
OF NNAL IN URINE OF MOTHER AND NEWBORN
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Development of LC-MS/MS for NNAL in urine
• Simple sample preparation
• Rapid analytical time
• High sensitivity
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Enzyme treat• NNAL-glucuronides hydrol-ysis
• Time: 20h
Extraction• Liquid-Liquid extraction• Time: 1h
Derivatization• N-propyl derivatization• Time: 12h
Analysis LC-MS/MS• Analytical time: 30min / test
- Sample preparation
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LC-MS/MS analysis of NNAL
Blank Urine
LLOQ: 20 pg/mL
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LC-MS/MS analysis of NNALBefore enzyme treatment
After enzyme treatment
NNAL-glucuronides Concentration: NNAL concentration (After enzyme treatment) – NNAL (Before enzyme treatment)
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• Simple sample preparation
– Each detection of NNAL and NNAL-glucuronides
• Rapid analytical time
– Optimization of analytical column
• High sensitivity
– Optimization of sample preparation
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The End